Encore Vision has identified an innovative treatment for Presbyopia. The aim of the proposed phase I studies is to develop a topical ocular formulation of our co-drug to achieve therapeutic levels of active agent in the rabbit aqueous humor without adversely affecting cornea health and lens metabolism. Onset of Presbyopia leading to progressive loss of near vision after age of 40 presents with limited treatment options including eyeglasses, contact lenses, or Lasik surgery. According to Encore Visions working hypothesis, the age-dependent increase in protein sulfhydryl group oxidation (PSH to PSSR and PSSP) to form protein cross-links contributes to the age-dependent decrease in lens elasticity underlying the loss of accommodative amplitude. We have identified a proprietary amphipathic co-drug that restores the elasticity of the lens when applied topically to the eyes of 8-month-old mice. The co-drug elicits no acute toxicology in Draize testing in rabbits. The co-drug is cleaved by cellular esterases to release a pro-reductant, that when converted to active reducing agent by cellular oxidoreductases, increases mouse lens elasticity by decreasing the number of protein-disulfide bonds. The reducing agent is methylated for clearance in vivo. Oxidoreductase-dependent reduction of the pro-reducing agent requires energy-dependent maintenance of the redox balance with NAD+, NADH and NADP+, NADPH. The route for clearance of excess reducing agent uses S-adenosylmethionine (SAM) as the methyl donor. Therefore topical treatment with pro-reductant could potentially cause an energy drain as well as a reduction in SAM levels that in turn could affect other critical metabolic processes in the cornea and lens. The esterase-dependent cleavage of the co-drug also releases an intermediate to regenerate SAM. Our phase-I Specific Aim is to develop a formulation of our co-drug that ensures cornea health while preventing adverse changes in redox balance and SAM-dependent methylation potential in the lens. To achieve our aim we will complete the following tasks: Task 1. Using rabbits, determine, the effects topical ocular doses of our co-drug formulation on cornea barrier function (Fluorescein) and cornea thickness (pachymetry). If permanent changes in cornea health are observed, lower dose formulations will be prepared and tested; Task 2. Determine the ocular pharmacokinetics of our co-drug, its metabolites, SAM-cycle intermediates and redox balance. For task 2, cornea perfusion and lens culture will be used to define corneal and lenticular pharmacokinetics that will then be compared to aqueous humor levels after topical ocular dosing of rabbits. PUBLIC HEALTH RELEVANCE: Onset of Presbyopia, the progressive loss of near vision after age of 40, presents with limited treatment options including eyeglasses, contact lenses, or Lasik surgery. Encore Vision's goal is to develop a safe topical ocular drop as an option for the treatment of presbyopia.